At the present time, there are a number of devices commercially available that allow for external monitoring of glucose levels of urine and blood. These devices, however, do not allow for continuous monitoring, and they require a high degree of patient compliance in order to be effective.
Much research has been directed toward the development of a glucose sensor that would function in vivo as an aid, for example, in the treatment of diabetes mellitus. An implantable glucose sensor that would continuously monitor a patient's blood glucose level could serve as a hypo- and hyperglycemia alarm, and would provide physicians with more accurate information in order to develop optimal therapy. In addition, such a sensor would make possible the development of a "closed loop" insulin delivery system in which a pump delivers insulin as needed, rather than on a programmed basis.
Implantable glucose sensors have been developed based on both optical and electrochemical principles. Schultz and Mansouri have disclosed one version of an optical sensor (J. S. Schultz and S. Mansouri, "Optical Fiber Affinity Sensors," Methods in Enzymology, K. Mosbach, Ed., Academic Press, New York, 1988, vol. 137, pp. 349-366). An impediment to the commercial development of an optical sensor of the type disclosed by Schultz and Mansouri has been the difficulty of producing such devices on a commercial basis.
Electrochemical glucose sensors, on the other hand, can be produced using techniques common in the semiconductor industry. The ability to mass produce electrochemical glucose sensors using known commercial techniques gives them a cost advantage over optical sensors. As a consequence, considerable research has been directed toward the development of an in vivo electrochemical glucose sensor. An excellent summary of the issues relating to the development of implantable electrochemical glucose sensors has been published by Turner and Pickup (A. P. F. Turner and J. C. Pickup, "Diabetes Mellitus: Biosensors for Research and Management," Biosensors, 1, 85-115 (1985)).
The most favored configuration to date for an electrochemical glucose sensor involves the use of one or two enzymes to catalyze the reaction between glucose and another molecule in order to generate an electrical signal. Typically glucose oxidase is used to catalyze the reaction between glucose and oxygen to yield gluconic acid and hydrogen peroxide, as follows: ##STR1## The hydrogen peroxide generated may be detected directly or it may be decomposed by a second enzyme, catalase, in which case the sensor will measure oxygen consumption by the reaction involving glucose oxidase.
The presence of an excess of molecular oxygen, relative to molecular glucose, is necessary for the operation of a glucose oxidase based glucose sensor. This presents a problem in the design of such sensors, since the concentration of oxygen in the subcutaneous tissue is much less than that of glucose. As a consequence, oxygen can become a limiting reactant, giving rise to an "oxygen deficit" problem. Some provision should therefore be made to allow operation of the sensor in an environment with an excess of oxygen.
Many attempts have been made to utilize membranes of various types in an effort to ratio the diffusion of oxygen and glucose to the sensing elements of glucose oxidase based glucose sensors to address the "oxygen deficit" problem. The simplest approach to controlling diffusion has been to use a macroporous or a microporous membrane. For example, in U.S. Pat. No. 4,759,828, Young et al. disclose the use of a laminated membrane with an outer microporous membrane having a pore size of 10 to 125A to limit the diffusion of glucose molecules. One immediate problem with macroporous or microporous membranes, however, is that the sensing element of the sensor is exposed to the environment of the body and is therefore subject to fouling. Young et al. attempted to obviate this problem by the use of a second inner membrane to exclude passage of fouling substances to the sensing element. This design creates additional problems in that transport to the sensing element through the second membrane must not be hindered. Also, because two membranes are necessary, each membrane must be extremely thin so that measurement times are not unduly long.
Another approach has been to utilize a membrane element that contains discrete hydrophilic and hydrophobic domains. In U.S. Pat. No. 4,484,987, Gough discloses a composite membrane in which an immiscible hydrophilic material is physically incorporated in a hydrophobic matrix. The purpose of such a membrane is to achieve a favorable balance between oxygen diffusion through the hydrophobic and hydrophilic matrices and glucose diffusion only through the hydrophilic domains. The effectiveness of such a membrane depends upon the relative amounts of the hydrophilic domains within the hydrophobic matrix. Such membranes are difficult to fabricate reproducibly, particularly on the scale of a glucose sensor meant for implantation within the body. Also, because of the discontinuous nature of the membranes disclosed in Gough '987, physical properties are compromised.
In U.S. Pat. No. 4,890,620, Gough discloses a further elaboration of this concept, utilizing a "two-dimensional" sensing electrode. Here the "membrane" element is physically constructed so that oxygen and glucose diffuse to the sensing electrode at right angles to one another, one direction favoring oxygen diffusion and the other favoring glucose diffusion. While a glucose sensor incorporating the diffusion element of Gough '620 may be useful for research purposes, it would be difficult to fabricate on a commercial scale because of its complexity. Additionally, constraints would be placed upon the size and configuration of the sensor in order to allow for diffusion to the sensing electrode from two directions.
Gernet et al. and Shichiri have recognized the above-mentioned difficulties and have utilized a single homogeneous membrane composed of a hydrophobic polyurethane (S. Gernet, et al., "Fabrication and Characterization of a Planar Electrochemical Cell and its Application as a Glucose Sensor," Sensors and Actuators. 18, 59-70 (1989); M. Shichiri, "Glycaemic Control in Pancreatectomized Dogs With a Wearable Artificial Endocrine Pancreas," Diabetologia, 24, 179-184 (1983)). While a homogeneous hydrophobic membrane eliminates many of the difficulties mentioned above, it does not provide an optimum balance between oxygen and glucose transport to an electrochemical glucose sensor, nor is it possible to tailor the properties of the homogeneous hydrophobic polyurethane membrane utilized by Gernet et al. and Shichiri to match the design requirements of electrochemical glucose sensors.